Abstract Regular physical activity (PA) improves cardiovascular health, but majority of adults do not engage in enough of it. A substantial proportion (48?71%) of variance in PA adherence is attributed to genomic variability, and several single nucleotide polymorphisms (SNPs) have been identified. The impact of this research will be limited, however, until we understand how these SNPs influence PA adherence. Understanding the psychological phenotype that mediates genetic influence on PA adherence can provide new insights about how to improve PA adherence when someone is genetically predisposed to be less physically active. Our objectives are to examine the SNPs in brain-derived neurotrophic factor gene (BDNF) as predictors of adherence to a PA promotion intervention and to identify a psychological phenotype that mediates this genetic effect on behavioral phenotype (i.e., PA adherence). We propose to test our conceptual model in a secondary analysis and a pilot study: Genetic Variation ? Affective Response to PA ? PA adherence. In this model, PA adherence is conceptualized as moderate to vigorous PA during- and post-intervention controlling for baseline moderate to vigorous PA. Aim 1 of this proposal seeks to examine the moderating effects of BDNF SNPs (rs6265 and rs12291063) on response to a PA promotion intervention in a secondary data analysis of 3899 overweight middle-aged adults from the Look AHEAD trial. The Look AHEAD is a randomized controlled trial that examined the effect of intensive lifestyle intervention, including weight loss and PA, relative to diabetes support and education (i.e., control), on cardiovascular outcomes. Aim 2 of this proposal seeks to examine the association between BDNF (rs6265) and affective response to PA. We will conduct a pilot study among 60 previously sedentary overweight middle-aged adults. Aim 3 of this proposal seeks to examine affective response to PA as a mediator between BDNF (rs6265) and PA adherence in the context of our pilot study. In the pilot study, we will conduct a longitudinal observation study. At baseline, we will collect blood sample for genotype and measure affective response to PA while walking on a treadmill for 30 minutes. Then, all participants will be encouraged to increase PA using a print-based PA promotion program for the next 6 months. Moderate to vigorous PA rate will be measured for seven days via accelerometer at baseline, month 3 and month 6. This study will be the first to examine affective response to PA as a mediational phenotype using a full model: Genetic Variation ? Affective response to PA ? PA adherence. Funding of this fellowship will provide the applicant training in genotyping, affect assessment, and accelerometry. Next steps in this research agenda include extension of this model to larger samples and more SNPs to ultimately develop a novel behavioral intervention that uses individuals' SNP status to optimize affective response to PA to improve PA adherence.